The initiation and maintenance of ingestive behavior is co-determined by metabolic and non-metabolic factors. Among the latter, environmental cues as well as reward, cognitive and emotional factors play an important role, particularly in human food intake in the modern world. These non-homeostatic factors are processed mainly in cortico-limbic structures such as the prefrontal cortex, amygdala, and ventral striatum. An important issue is to understand how and where metabolic and non-metabolic factors are integrated to drive food intake. The proposed work focuses on one aspect of this issue by examining the anatomical, neurochemical, and functional relationship between the ventral striatum and the hypothalamic peptidergic circuits implicated in the homeostatic regulation of energy balance. In Aim 1, we identify hypothalamic targets of ventral striatal projections involved in the robust intake of specific foods induced by chemical manipulations within the nucleus accumbens or ventral pallidum, using Fos expression, neuronal tracing, immunohistochemistry, and in situ hybridization. In Aim 2 we hypothesize that chemical manipulations in the nucleus accumbens stimulate further food intake and override normal homeostatic controls in fully satiated rats by acting on orexigenic and/or anorexigenic hypothalamic signaling systems. We test this by using pharmacological experiments with selective antagonists and agonists against "feeding" peptide receptors, anatomically localized immunotoxic lesions, and murine knockout models. In Aim 3 we hypothesize that ventral striatum D hypothalamus projections play an important role in the acute hyperphagic response to palatable foods and in the development of obesity with chronic exposure to palatable diets. To this end, we use two different chronic lesion models that interrupt specific components of ventral striatal-hypothalamic circuitry, and measure both "liking" and "wanting" aspects of food intake as well as adiposity and body weight. The results will be important for (1) gaining detailed anatomical and neurochemical insight into the relationship between reward and homeostatic neural systems, (2) the development of a conceptual framework of how the different psychological processes involved in food reward are neurologically organized, and (3) the development of pharmacological and behavioral therapeutic tools to counteract "common" obesity in a world of plenty.